Small-Molecule Inhibitors of the m7G-RNA Writer METTL1

  • ACS Bio Med Chem Au. 2023 Dec 12;4(2):100-110. doi: 10.1021/acsbiomedchemau.3c00030.
Francesco Nai  1 ,  Maria Paula Flores Espinoza  1 ,  Annalisa Invernizzi  1 ,  Pablo Andrés Vargas-Rosales  1 ,  Olga Bobileva  2 ,  Marcin Herok  1 ,  Amedeo Caflisch  1
Affiliations
  • 1. Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • 2. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
PMID: 38645929 DOI: 10.1021/acsbiomedchemau.3c00030
Abstract

We discovered the first inhibitors of the m7G-RNA writer METTL1 by high-throughput docking and an enzymatic assay based on luminescence. Eleven compounds, which belong to three different chemotypes, show inhibitory activity in the range 40-300 μM. Two adenine derivatives identified by docking have very favorable ligand efficiency of 0.34 and 0.31 kcal/mol per non-hydrogen atom, respectively. Molecular dynamics simulations provide evidence that the inhibitors compete with the binding of the cosubstrate S-adenosyl methionine to METTL1. We also present a soakable crystal form that was used to determine the structure of the complex of METTL1 with sinefungin at a resolution of 1.85 Å.

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